3prm
From Proteopedia
Structural analysis of a viral OTU domain protease from the Crimean-Congo Hemorrhagic Fever virus in complex with human ubiquitin
Structural highlights
Function[UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] Publication Abstract from PubMedCrimean-Congo hemorrhagic fever (CCHF) virus is a tick borne ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. With fatality rates for CCHF ranging up to 70% based on several factors, CCHF is considered a dangerous emerging disease. Originally identified in the former U.S.S.R. and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recent reports have identified a viral homologue of the ovarian tumor protease superfamily (vOTU) within its L-protein. This protease has subsequently been implicated in down-regulation of the interferon type 1 immune response through cleavage of post-translational modifying proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15). Additionally, homologues of vOTU have been suggested to perform similar roles in the ssRNA (+) Arteriviruses. By utilizing X-ray crystallographic techniques, the structure of vOTU covalently bound to ubiquitin propylamine, a suicide substrate of the enzyme, was elucidated to 1.7 A revealing unique structural elements that define this new subclass of the OTU superfamily. In additions, kinetic studies were carried out with aminomethylcoumarin (AMC) conjugates of monomeric Ub, ISG15, and Neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) substrates in order to provide quantitative insight into vOTU's preference of Ub and Ub-like substrates. Structural analysis of a viral ovarian tumor domain protease from the Crimean-Congo Hemorrhagic Fever virus in complex with covalently bonded ubiquitin.,Capodagli GC, McKercher MA, Baker EA, Masters EM, Brunzelle JS Dr, Pegan SD Dr J Virol. 2011 Jan 12. PMID:21228232[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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